17-thio-5-androstene-3-ols



17-THIO-5-ANDROSTENE-3-OLS Raymond M. Dodson, Park Ridge, and Paul B. Sollman, 'Skokie, Ill., assignors, by mesne assignments, to G. D. Searle & C0., Skokie, 11]., a corporation of Delaware Application February 1, 1955, Serial No. 485,606

No Drawing.

8 Claims.

Y OH: 1

wherein X is hydrogen or a lower alkanoyl radical and Y is a member of the group consisting of T\HSH fi 'sH (a) viii-S (lower alkyl) S (lower alkyl) (a) :S (lower alkanoyl) (13) and :8. The term lower alkanoyl is defined herein as an acyl radical derived from a lower alkanoic acid. The lower alkanoyl radicals embraced in this definition include formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and branched-chained isomers thereof.

It has been discovered that the 17-thiols, 17-thioethers, 17-thioketones, and 17-acylthio derivatives which constitute this invention can be prepared from readily available and relatively abundant starting materials such as dehydroisoandrosterone. For example, the steps which comprise reducing dehydroisoandro-sterone acetate with sodium borohydride to the 3-monoacetate of S-androstene- 3B,l7;3-diol, esterification of the l7fi-hydroxyl group with p-toluenesulfonyl chloride, and selective hydrolysis at the ester group at position 3 lead to the l7/3-p-toluenesulfonate of -androstene-3fi,l7/8-diol. The ester grouping in this compound is of the neopentyl type and by analogy with similar compounds, such as the neopentyl halides, would be expected to be resistant to replacement by another negative group. Surprisingly, when the ester is treated with sodium hydrosulfide, replacement of the ester grouping occurs readily, with the introduction of a thiol group in the u-configuration and the formation of 3fi-hydroXy-5-androstene-l7u-thiol. The corresponding disulfide is obtained as a by-product in this reaction, as disclosed in greater detail in the pertinent example.

nited States Patent W p ICE Mercaptan derivatives which have the fi-configuration of the thiol group are conveniently obtained from dehydroisoandrosterone by another method which has been newly developed. When the dibenzylrnercaptole of dehydroisoandrosterone, described in Journal American Chemical Society, 70, 1256 (1948) is treated in liquid ammonia with metallic sodium, the reaction product is the thioketone of the following structure S CH3 Reduction of this compound with sodium borohydride yields 3fi-hydroxy-S-androstene-l7B-thiol.

By contacting the mercaptans described herein with lower alkanoic acid anhydrides, conveniently in pyridine solution, thioesters are obtained in which the hydrogen of the thiol group is replaced by the acyl radical derived from a lower alkanoic acid. The compounds obtainedthereby are of the type wherein A and A are acyl radicals derived from lower alkanoic acids. A and A accordingly represent formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and branched chain isomers of the foregoing. Other important compounds of this invention are the l7-thioethers which have the structural formula SR CH;

wherein X is hydrogen or a lower alkanoyl radical and R is a lower alkyl radical. R can be selected from methyl, ethyl, and straight or branched-chain propyl, butyl, amyl, and hexyl. One method of preparing these compounds is by alkylation of the corresponding mercaptan. Suitable reaction media for carrying out the alkylation reaction are mixtures of a lower alkyl iodide, a sodium alcoholate, and a lower aliphatic alcohol. Thioethers having a lower alkylthio group in both the uand ,B-configuration at position 17 can be prepared by alkylating the corresponding mercaptan of the same configuration. An alternative method for preparing a thioether having the fi-configuration is exemplified by the conversion of l7ot-methylthio-5- androsten 3,8 01 to 17/3 methylthio-S-androstm-35-01.

This transformation is achieved with the aid of an isomerization process carried out on a sulfone derivative. When 17a-methyIthio-S-androsten-3fl-ol is oxidized with two molecular equivalents of perbenzoic acid, the product is 17mmethylsulfonyl-S-androsten-3fi-ol. Under the influence of potassium tert.-butoxide, this sulfone is isomerized to 175- methylsulfonyl-S-androsten-BB-ol having the following formula H3 CH3 Reduction of this compound with lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran then yields the same 17 3-methylthio-5-androsten-36-01 that is obtained by the direct alkylation of 3,8-hydroxy-5-androstene-l 7B-thiol.

The compounds which constitute this invention are useful in chemotherapeutics. They are effective antagonists of naturally occurring steroid hormones which may be regarded as oxygen analogs. For example the claimed compounds have been found to antagonize the localized effects of testosterone. They also possess one of the specific useful properties of the adrenocortical hormones in that they are effective in the prevention of traumatic shock. Their alleviation of stress states of this type is not accompanied by the wide diversity of side effects observed with the use of such naturally occurring hormones as cortisone and hydrocortisone. The thioethers of this invention form sulfonium salts which have valuable antibacterial properties and are effective against Bacillus subtilis. The mercaptans of this invention are useful asanalytical reagents. They give characteristic precipitates with heavy metal ions, and the precipitated salts obtained with lead are useful for both the qualitative and quantitative analysis of this element.

This invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein. It will be apparent to those skilled in the art that many modifications in materials and methods can be made without departing from the scope of this invention. In these examples, temperatures are given in degrees centigrade and quantities of materials in parts by weight.

Example 1 A solution of 25 parts of dehydroisoandrosterone acetate in 850 parts of methanol is cooled in an ice bath to 8 C. and treated by the addition of 12.5 parts of sodium borohydride dissolved in 250 parts of methanol. The mixture is kept in an ice bath for 10 minutes and is then treated with small portions of acetic acid until the evolution of gas is complete. An additional 50 parts of acetic acid and 3000 parts of Water is then added and the precipitated product is filtered, washed with water and dried. Recrystallization of this product from aqueous acetone yields the purified 3-monoacetate of 5-androstene-3fl,17fldiol, melting at 147-148 C.

Example 2 ridine and 22 parts of p-toluenesulfonyl chloride is allowed to stand for about 18 hours at 65 C. It is then poured tural formula CH; oso=on= CH3 CHsCO 0 Example 3 A solution prepared from 30 parts of 3B-acetoxy-17B-ptoluenesulfonoxy-S-androstene, 310 parts of dioxane, parts of methanol, and 46 parts of a solution prepared from equal weights of sodium hydroxide and of water is allowed to stand at room temperature for 2 hours. The mixture is then diluted with 600 parts of water and the crystalline precipitate of 17/3-p-toluenesulfonoxy-5-androsten-3fl-ol is collected on a filter, Washed with Water, and dried. This product melts at 102103 C., then solidifies and remelts at -132 C. It has the structural formula o-sw-Q-om CH3 Example 4 A solution of sodium hydrosulfide is prepared by passing a stream of hydrogen sulfide gas through a mixture of 520 parts of ethylene glycol monoethyl ether and 35 parts of sodium methoxide, until substantially all of the sodium methoxide is consumed, as evidenced by the completion of the exothermic reaction. About 1 hour is a convenient period of time for this reaction.

This solution of sodium hydrosulfide is mixed with 14 parts of l7fi-p-toluenesulfonoxy-5-androsten-3f3-ol and heated under reflux for 5 hours. The mixture is then poured into 2500 parts of water and partitioned with ether. A product insoluble in both the aqueous and organic phases is collected on a filter and washed with water. This product is the disulfide melting at 265-268 C. and having the structural formula HO OH trated to a small volume and diluted with methanol. A crystallizate of 3fl-hydroxy-5-androstene-17a-thiol separates and is collected on a filter and washed with methanol. This product melts at 142144 C. It has the structural formula SIH Example 5 SCH: CH3

Example 6 A mixture of 6 parts of 3 3-hydroxy-5-androstene-17athiol, 96 parts of anhydrous propyl alcohol, 1.9 parts of sodium propoxide and 3.8 parts of propyl iodide is heated under reflux for a period of 3 hours. The reaction mixture is then poured, with stirring, into several times its volume of water and the precipitated product, 17w propylthio-S-androsten-3,6-ol, is collected on a filter. It is purified by recrystallization from methanol. This compound has the structural formula SCgH1 CH:

Exantpl'e A solution prepared from 24 parts of 17a-methylthio- 5-androsten-3B-ol, 195 parts of butanone, and 205 parts of methyl bromide is placed 'in a tightly sealed reaction vessel, and allowed to stand for 16 hours at 65 C. The

material which crystallizes from the solution is removed by filtration and is recrystallized from water. It is further purified by dissolving itin' 1000 parts of hot alcohol and precipitating by the addition of 1000 parts of peroxide-free ether.

bromide of 17a-methylthio-5-androsten-3fl-ol. It melts This compound is the metho-..

3 with decomposition at 188-189 C. and has the following structural formula S(CHa)gBr CH3 Example 8 A suspension of 5.19 parts of the dibenzylme'rcaptole oi dehydroisoandrosterone in parts of liquid ammonia is treated with a total of 5.2 parts of sodium, added in portions at 10 minute intervals over a period of 2 hours. Ammonium chloride (15 parts) and ether (210 parts) are then added and the slurry is stirred for about 16 hours. About 500 parts of water and 15 parts of ammonium chloride are added and the ethereal phase is separated and combined with an ether extract of the aqueous phase. The combined ethereal solution is washed with water and then concentrated to a residual pink oil. A solution of this oil in benzene is poured on a silica gel chromatography column. Elution with benzene yields first a small amount of bibenzyl melting at 45-48 C. Further elution with a 2 volume percent solution of ethyl acetate in benzene aifords 3fi-hydroxy-5-androstene-l7- thione. After recrystallization from a mixture of benzene and petroleum ether, this compound melts at 168170 C. It has the structural formula S CH I Example 9 A solution of 1.34 parts of 3 fl-hydroxy-S-androstene-17- thione in 52 parts of acetic acid is treated by the addition of 3 parts of concentrated hydrochloric acid. After the mixture has been allowed to stand at room temperature for about 30 minutes, it is diluted with water. The precipitated product is collected and recrystallized from a mixture of benzene and petroleum ether and then from aqueous ethanol, giving dehydroisoandrosterone acetate of melting point 170-171 C.

Example 10 A solution prepared from 8 parts of SB-hydroxy-S-androstene-l7-thione, 240 parts of methanol, 1.5 parts of sodium methoxide and 3.8 parts of methyl iodide is allowed to stand for 3 hours at room temperature. The product obtained by diluting the mixture with water is collected on a filter. By several recrystallizations from aqueous methanol there is obtained l7-methylthio-5,l6-

7 androstadien-3 8-ol melting at 164166 C. This compound has the structural formula SCHs CH fi Example 11 A solution of 2 parts of 3fi-hydroxy-5-androstene-17- thione in 48 parts of methanol is added to a solution of 4 parts of sodium borohydride in 32 parts of methanol. After 10 minutes at room temperature, the mixture is acidified by the cautious addition of small portions of 10% acetic acid. The precipitate formed by dilution with Water is collected on a filter and dried. By recrystallization .from a mixture of ether and petroleum ether and then from methanol, there is obtained 3,8-hydroxy-5-androstene-l7B-thiol melting at 174.5175.5 C. and having the structural formula SH CH3 Example 12 SCHa CH3 Example 13 A mixture prepared from parts of 3B-hydroxy-5- androstene-lm-thiol, 1000 parts of butanol, 3.3 parts of sodium butoxide and 6.2 parts of butyl iodide is heated under reflux for 3 hours. The reaction mixture is poured, with stirring, into several times its volume of water and the precipitated product is collected on a filter. Purified l7;8-butylthio-S-androsten-35-01 is obtained by recrystallization of this product from methanol.

. has the structural formula SC4Hv The reaction mixture is diluted with This compound 8 Example 14 A mixture of 5 parts of 3fi-hydroxy-5-androstene-17f?- thiol, 30 parts of pyridine and 25 parts of valeric anhydride is heated on a steam bath for 2 hours and is then allowed to stand at room temperature for 20 hours. The reaction mixture is poured, with stirring, into parts of Water, causing the formation of a precipitate of the valerate of 171S-valerylthio-5 -androsten-3 3-01. This divaleryl derivative has the structural formula SO 0 (OH2)a H: C H] CH3 CH2 3C O 0 Example 15 A stirred solution of 9.6 parts of l7a-methylthio-5- androsten-3fi-ol in 880 parts of benzene is treated over a period of 30 minutes by the gradual addition of a 0.3 molar solution of perbenzoic acid in benzene containing a total of 8.28 parts of perbenzoic acid. After an additional hour the solution is Washed with sodium bicarbonate solution and with water and then concentrated to dryness. The residue in benzene solution is reprecipitated by the addition of petroleum ether. This product is then crystallized several times from aqueous alcohol and finally from a mixture of benzene and petroleum ether to give purified 17u-rnethylsulfonyl-S-androsten- 35-01 melting at 225-227 C. It has the structural formula CH3 O==0 cm f? Example 16 Five parts of l7u-methylsulfonyl-5-androsten-3/3-ol is dissolved in a solution prepared from 3.6 parts of potassium and 70 parts of tert.-butanol. This reaction mix ture is heated under reflux for 17 hours and then concentrated by distillation to about two-thirds of its original volume. The remaining solution is poured into about 300 parts of ice Water and this mixture is acidified by the addition of 15 parts of concentrated hydrochloric acid. The precipitated product is collected on a filter, Washed with water, dried, and recrystallized from ethyl alcohol or from ethyl acetate. In this manner there is obtained the isomerized sulfone, 17B-methylsulfonyl-5- androsten-BB-ol melting at 242-244 C. This compound has the structural formula CH2 CH3 9 Example 17 CHaOO 0 Example 18 A quantity of tetrahydrofuran is purified for this reaction. This is conveniently accomplished by drying it over sodium hydroxide and distilling it successively from sodium and from lithium aluminum hydride. A solution of 2.9 parts of 17B-methylsulfonyl-S-androsten-3,8-01 in 27 parts of tetrahydrofuran is added to a solution of 6 parts of lithium aluminum hydride in 90 parts of tetrahydrofuran, and the reaction mixture is heated under reflux for 16 hours. Unreacted lithium aluminum hydride is decomposed by the addition of ethyl acetate. Water (50 parts), 10% sulfuric acid (300 parts), and water (500 parts) are added in succession, with efiicient stirring. The suspension is extracted with a total of 700 parts of ether in three portions, and the washed ethereal solution is concentrated to about of its original volume. The solvent mixture remaining at this concentration contains a large percentage of tetrahydrofuran. Water is added, and the crude solid product which precipitates is collected on a filter and washed. This crude product is extracted with a total of 620 parts of benzene in two portions. Some unreacted 17/3-methylsulfonyl-5- androsten-3B-ol remains undissolved and is recovered by filtration. The benzene solution is poured on a chromatography column prepared from 105 parts of silica. By elution with a volume per cent solution of ethyl acetate in benzene there is obtained 17,8-methylthio-5- androsten-Bfi-ol. After recrystallization from aqueous methanol this product melts at 150 C. and is identical with the product of Example 12. By elution of the chromatography column with a 30 volume per cent solution of ethyl acetate in benzene, an additional quantity of unreacted 17,8-methylsulfony1-5-androsten-3B-ol is recovered.

Example 19 A solution prepared from 3 parts of 3/3-hydroxy-5-androstene-17a-thiol, parts of pyridine and 15 parts of acetic anhydride is allowed to stand at room temperature. During the first hour of reaction time, and especially during the first few minutes, the presence of a free mercaptan in the reaction mixture can be demonstrated by removing a drop of the solution and treating it with one drop of a saturated solution of lead acetate in methanol, whereupon a yellow precipitate of a lead salt of the mercaptan forms. After about an hour, this test becomes very faint. After 16 hours the reaction mixture is poured, with stirring, into 50 parts of water and the crystalline precipitate is collected on a filter. By recrystallization from petroleum ether and then from aqueous ethanol,

there is obtained the purified acetate of 17a-acetylthio-5- androstene-Zifl-ol melting at 152-153 C. This diacetyl derivative has the structural formula S OOCH3 OHsCOO What is claimed is:

1. A compound having the structural formula CHa Y CH3 I wherein X is a member of the group consisting of hydrogen and lower alkanoyl radicals and Y is a member of the group consisting of E-S (lower alkanoyl) (a) and=S.

2. A compound having the structural formula 3. 3fihydroxy-5-androstene-17,8-thiol.

4. 3B-hydroxy-5-androstene-17a-thiol.

5. A compound having the structural formula SCH: OH;

6. 176-methylthio-5-androsten-3B-ol. 7. 17a-methyIthiO-S-androsten-3 3-ol. 8. 3 3-hydroxy-5-androstene-17-thione.

References Cited in the file of this patent UNITED STATES PATENTS 2,550,702 Levin May 1, 1951 2,598,653 Wettstein May 27, 1952 2,598,654 Wettstein May 27, 1952 2,609,378 Rosenkranz Sept. 2, 1952 2,697,108 Rosenkranz Dec. 14, 1954 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 